A number of diseases are associated with hyperproliferation of cells, including psoriasis, the ichthyoses, cancer and cutaneous viral infections. Psoriasis is a chronic inflammatory disease characterised by hyperproliferation and impaired differentiation of keratinocytes. Currently, the symptoms of psoriasis are treated in a number of ways, including topical administration of retinoids to the patient. Other diseases such as acne vulgaris and photoageing also respond to retinoid therapy and are believed to involve additional retinoid-mediated mechanisms.
Retinoids have also been used for both treatment and prevention of the development of cancers (e.g. treatment of acute promyelocytic leukaemia and prevention of the development of cutaneous malignancies in renal transplant patients).
Current retinoid therapy is based upon the effect of carboxylic acid derivatives of vitamin A (in particular, retinoic acid, the endogenously active compound) which are able to transcriptionally regulate target genes. Exposure to retinoic acid and retinoids results in proliferating cells withdrawing from the cell cycle and differentiating in response to retinoic acid-induced transcription of a possible excess of 300 target genes. This is a “forced” differentiation that represents a reprogramming of the normal cell fate and can be considered as an instructive differentiation. Treatment with retinoids has been found to be effective in controlling psoriasis, tumours and in relieving the symptoms of photoageing.
However, despite the beneficial effects of retinoid treatment, its benefits are limited by potentially serious adverse effects including hepatotoxicity, hyperlipidaemia, inhibition of bone growth, cutaneous irritation, photosensitivity, alopecia and teratogenicity (Kemmett and Hunter, 1988, Hospital Update. March 1988, pp 1301-1313). These effects are related to the pharmacological dosages needed to achieve a therapeutic response. To date, the search for alternative retinoids and methods to use retinoids has produced only marginal reductions in the cutaneous adverse effects.
It is therefore an aim of the present invention to provide for a method of treatment of hyperproliferative diseases and diseases associated with photoageing which avoids the adverse effects of retinoid administration.